The dramatic rise in the prevalence of antibiotic resistance among bacteria requires the discovery and development of new antimicrobials to treat infections caused by these organisms. Of major health concern are drug resistant infections caused by Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus, multidrug resistant Streptococci pneumoniae, Neisseria gonorrhoeae, and Mycobacterium tuberculosis, pan-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii (Fischbach et al. Science 2009, 325 (5944), 1089-1093; Goldston et al. Suicide Life Threat. Behav. 2010, 40(3), 245-256; Nicasio et al. Pharmacotherapy 2008, 28 (2), 235-249). There is also a need for new therapeutic agents to treat biodefense pathogens.
The rise of these organisms comes at a time when the pipeline for the development of new antibiotics has become sparse (Fattori et al. Drugs R. D. 2008, 9 (4), 217-227; Ejiri et al. Org. Lett. 2010, 12 (8), 1692-1695). Moreover, the application of bacterial genomics coupled with high throughput screening technologies has been met with limited success (Lange, et al. Curr. Pharm. Design 2007 13, 3140-3154; Mills, Biochem. Pharmacol. 2006 71, 1096-1102; and Payne, et al. Nat. Rev. Drug Disc. 2007 6, 29-40). In this context, it is prudent to consider what has been the most successful strategy in antibacterial drug discovery, namely the synthetic modification of natural products to produce new semisynthetic antibiotics (Fischbach et al. Science 2009, 325 (5944), 1089-1093; Wright et al. Trends Mol. Med. 2007, 13 (6), 260-270; Nakasako et al. J. Mol. Biol. 1999, 291 (1), 117-134).
Spectinomycin is an aminocyclitol antibiotic that specifically inhibits bacterial protein synthesis by binding to 30S ribosome at a unique site that is highly conserved across bacterial pathogens (Carter et al. Nature 2000, 407(6802), 340-348; Borovinskaya et al. ACS Chem. Biol. 2007, 2 (8), 545-552; Wirmer et al. Meth. Enzmol. 2006, 415, 180-202). Although spectinomycin is potent in cell free assays its clinical use is restricted to second line treatment for Neisseria gonorrhoeae infections (McCormack et al. Annals of internal medicine 1976, 84 (6), 712-716; Reyn et al. Br. J. Vener. Dis. 1973, 49 (1), 54-59; Zenilman et al. J. Infect. Dis. 1987, 156 (6), 1002-1004. Over 25 years ago, attempts to develop spectinomycin analogs led to the discovery of trospectinomycin, which progressed into late stage clinical trials before being abandoned by Upjohn.
Despite advances in antimicrobial research directed to semisynthetic analogs of natural products, there remains a significant need for antibiotic compounds that are potent, efficacious, and effective in the treatment of infectious disease associated with infection by gram positive and gram negative bacteria, particularly for broad spectrum antibiotics and for use against resistant bacterial strains. These needs and other needs are satisfied by the present invention.